6-methyl analogues of cortisone, hydrocortisone and 21-esters thereof



United G-METHYL ANALOGUES OF CORTISONE, HYDRO- CORTISONE AND 21-ESTERS THEREOF George B. Spero, Kalamazoo Township, Kalamazoo County, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application November 23, 1956 Serial No. 623,768

8 Claims. (Cl. 260397.45)

---OH ---OH CH CH3 O O l O I HO CH II CH CH H OR" CH OR" a 2 0 0 C=O CH CH 5 CH3 IV H6 Ha III wherein R is an alkylene radical containing not more than eight carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least two and not more than three carbon atoms, R is selected from the group consisting of 11 ,B-hydroxy and 11- keto, and wherein R" is hydrogen or acyl, the acyl group being of an organic carboxylic acid preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

The process of the present invention comprises: treating an 11-oxygenated-Su,6m-oxido-17u,21-dihydroxyallopregnane-3,20-dione 3,20-bis-(alkylene ketal) (I) with a methyl metal compound, preferably a methyl metal halide and specifically a methyl Grignard reagent to give the corresponding 11-oxygenated-5oc,17a,21 trihydroxy 65- methylallopregnane-3,ZO-dione 3,20-bis-(alkylene ketal), (II); hydrolyzing with acid in a suitable solvent the thus tes 2,897,217 Patented July 28, 1959 ice obtained diketal (II) to yield 11-oxygenated-5u,17a,21-trihydroxy-6 3-methyla1lopregnane-3,20-dione (I11) and de-' hydrating the thus obtained 1l-oxygenated-ia,17a,21 -trihydroxy-Gfl-methylpregnane-3,20-dione (III) with a base or an acid to obtain ll-oxygenated 6-methyl-17a,21-dihydroxy-4-pregnene-3,20-dione (IV). Large amounts of base or acid produce the 6ot-epin1er, ll-oxygenated-6amethyl-17a,2l-dihydroxy-4-pregnene-3,20-dione; smaller amounts of acid or base, so that the reaction mixture is near neutral results in the 6,8-epimer, ll-oxygenated-GB- methyl-17;1-dihydroxy-4-pregnene 3,20 dione, which can be converted with acid or base by an additional step to the u-epimer. Using in the first step of the reaction other metal halides, dialkyl cadmium compound, alkyl and phenyl cadmium halides, aryl and alkyl calcium halides such as phenyl calcium iodide and especially alkyl and phenyl Grignards such as ethyl, propyl, butyl, phenyl magnesium bromide or iodide results in other 11- oxygenated-Sa,17a,21-trihydroxy-6 3-alkyl or GB-phenylallopregnane-3,20-diones which by the subsequent steps are converted to the corresponding ll-oxygenated 6-alkylor 6-phenyl-17a,21-dihydroxy-4-pregnene-3,20-diones.

The term ll-oxygenated here refers to ll-hydroxy and ll-keto.

It is an object of the instant invention to provide the 6-methyl analogues of cortisone and hydrocortisone and the 21-esters of these compounds. It is another object of the instant invention to provide a proc'essfor the production of 6-methyl analogues of cortisone, hydrocortisone, and the esters thereof as well as other 6-alkyland 6-phenyl analogues of cortisone and hydrocortisone, and the esters thereof. It is another object of the present invention to provide the intermediates, ll-oxygenated 5u,17a,2l-trihydroxy-6fl-methylallopregnane-3,20 diones, the 3,20-diketa1s thereof, especially 5a,11B,l7a,2l-tetrahydroxy-6,8-methylallopregnane-3,ZO-dione I 3,20-bis-(ethylene ketal) and esters thereof. It is a particular object to provide the highly potent 6a-methylhydrocortisone and a-methylcortisone. Other objects of this invention will be apparent to those skilled in the art to which this invention pertains.

The new compounds, G-methylhydrocortisone, 6-meth yl-cortisone, and the 21-esters thereof, are active adrenocortical hormones having glucocorticoid activity. They have the additional advantage of having low salt retention and in addition have anti-phlogistic activity which makes them valuable for oral and parenteral as well as topical use. In particular, the 6a-methyl epimers, 6amethyl-hydrocortisone and 6a-methylcortisone and 21- esters thereof are active in excess of hydrocortisone while the GB-methyl epimers can be easily converted to the 6oc-epimers by acid or base as shown in Example 17. In Table I a comparison of the glucocorticoid activity of these compounds with the standard hydrocortisone is shown:

TABLE r Ratio of glucocorticoid activity (hydroc0rtisone==1) 60L-1'1'16thy1hyd1OCOItiSOHe is essentially inactive as a mineral corticoid and has a systemic anti-phlogistic activity as measured by granuloma pouch test aboutthreetimes that of hydrocortisone.

In general the compounds of the present invention can be prepared for animal or human use by incorporating them in any one of several dosage forms suitable for such use. Such a dosage form would include the active ingredients plus a non-toxic carrier which may be either a solid material or a liquid. Bland carriers are of course much preferred for oral use. Examples of oral dosage forms are tablets, capsules, liquid suspensions or solutions. For the dosage forms which are particularly suitable for parenteral administration, a sterile diluent is, of course, necessary. When the active ingredients are to be used topically it can be prepared as an ointment, a bougie, a lotion or a jelly. When the intended use is the eye or ear, the compounds can be prepared in the form'of drops or an ointment. The compounds may also be prepared in an aerosol vehicle when the intended use is nasal. Examples of the most preferred dosage forms areas followsz' v Tablets for oral use especially suitable for the treatment of arthritis;

6 a-methylhydrocortisone milligrams '5 Lactose grains 3.3 Sucrose do- 0.04 Starch do 0.075 Calcium stearate do 0.02

Other dosages of the active ingredient, 6a-methylhy drocortisone can be used varying between 1.0 and 25 milligrams. In addition other ingredients may be incorporated in the tablet such as antibiotics, e.g, tetraeycline, chlortetracycline, oxytetracycline, chloramphe'ni col, penicillin, novobiocin, or the like, sulfa drug's, aspirin or vitamins.

An example for tablets for oral use containing aspirin is given below: p

50,000 tablets containing aspirin and 6a-methylhydrocortisone as the essential active ingredients are prepared from the following types and amount of ingredients:

Mixture-Part1:

Acetylsalicyclie acid granular USP stand. No. 40 mesh 33lbs. 1oz.

Mixture--Part II:

fia-methylhydrocortisone 386 grs. Color 1 1b., 6 oz.,'375 grs. Bolted starch 11 oz., 188 grs. Bolted talc 1 1b., 6 02., 375 grs.

For topical use, ointments are prepared illustratively as follows:

For the preparation of 500 pounds of an ointment, suitable for topical use, containing advantageously .neomycin and 6a-methylhydrocortisone as the essential active ingredients, the following types and amounts of ingredients are used:

A microerystalliue wax of hi h meltin int f V Sonneborn and Sons, Inc., New Yori, N .55. g p mm L Other antibiotics which may be used advantageously in .place of or with neomycin include poly myxin B sulfate,

bacitracin, gramicidin and tyrothricin. ,Actual potentiatron of polymyxin and neomycin is obtained by the addmon ofo -methylhydrocortisone.

Instead'of 6a. -methylhydrocortisone, 21-esters thereof, like the ZI-acetate, propionate, butyrate, henzoate,

. 4 phenylacetate, phenylpropionate, dineopentylacetate, tertiary butylacetate, trimethylacetate and other esters, as shown in the examples, may be used for parenteral administration. Furthermore the 6a-methylhydrocortisone may be substituted by 6a-methylcortisone, the Gift-methylhydrocortisone, 6,8-methylcortisone or 2l-esters thereof, such as mentioned before. Other 6 x-alkylhydrocortisones or fiu-alkyloortisones or the 6,8-alkyl analogues of hydrocortisone and cortisone such as 6ocor 6/8-ethyl-, 6zxor 6fl-propyl-, 600- or 6 8-butyl-, 611- or 6,8-isobutyland 6aor 6B-phenylcortisone and hydrocortisone can be used in the above compositions. The water soluble esters of polybasic acids and their salts are particularly suitable for parenteral use such as the sodium, phenylephrine, N-methylglucamin salt of 6a-methylhydrocortisone ZI-hemisuccinate, dimethylglutarate, tartrate, glycolate, or the like, in bufiered solution.

The preparation of the above compositions is carried out in conventional manner known in the art.

Similarly the 6u-alkyl epi F compounds, 6a-alkyl-lla, 17a,21-trihydroxy-4-pregnene-3,20-dione, may be prepared which has usage as an intermediate in the production of 6a-alkylcortisone esters, for example, by the oxidation of 6a-alkyl-epi F 21-acylates with chromic acid as shown in Example 20.

The starting material for the instant invention, 511,604- oxido 11 oxygenated-17a,21-dihydroxyallopregnane-3, ZO-dione 3,20-bis(ketals), are prepared by ketalization of cortisone, hydrocortisone, and epi F and subsequent treatment with an organic peracid as shown in detail in Preparations 1 through 3.

In carrying out the process of the present invention a 511,60: oxido 11 oxygenated 17a,2l dihydroxyallopregnane-3,20-dione 3,20-bis-(ketal) usually an ethylene ketal, dissolved in a suitable organic solvent, such as tetrahydrofuran, benzene, toluene, ethyl ether, propyi ether, or the like, with the higher boiling solvents such as tetrahydrofuran and benzene preferred, is reacted with a methyl metal compound especially a methyl metal halide such as methyl magnesium chloride, bromide, or iodide, methyl lithium, dimethyl cadmium, or the like. Other useful alkyl or aiyl metals and alkyl or aryl metai halides include the ethyl, propyl, butyl, pentyl, hexyl, phenyl, benzyl magnesium chloride, bromide or iodide, the methyl lithium, phenyl lithium, sodium or potassium compound, the phenyl calcium iodide, the alkyl cadmium halides and dialkyl cadmium compounds wherein the alleyl group has from one to six carbon atoms, and the like, with the methyl magnesium bromide and methyl magnesium iodide preferred. In the preferred embodiment of the instant invention, the reaction is started at room temperature or below, temperatures between zero and thirty degrees centigrade being preferred. After the addition of the methyl magnesium halide or other methyl metal halides, the temperature is raised and the reaction mixture is heated to about reflux temperature for a period of from one to 48 hours. In general, a large excess of the Grignard reagent (ten to 500 mole equivalents) is used. The temperature for the Grignard addition reaction is generaly between 25 to 100 degrees centigrade, with the preferred rangeof from sixty degrees Centigrade to the reflux temperature of the-mixture, i.e., about eighty to degrees centigrade.

I After the reaction is terminated, the reaction mixture is decomposed using neutral, rather thanacidic conditions. In the preferred embodiment of the invention, the reaction mixture is mixed with an aqueous saturated ammonium chloride solution, cooled with ice, and the resulting mixture is stirred for a period of several minutes to one hour. The aqueous and organic layers are then separted from each other. The organic phase is washed, dried and evaporated to give the crude ll-oxygenated- 5a.,170t,21 trihydroxy 6,6 methylallopregnane 3,20- dione 3,20 falkylene ketal), .which can be purified by conventional procedures, such as recrystallization and/or chromatography with organic solvents, as deemed necessary.

The thus obtained 1I-OXygenated-Sa,l7a,2ltrihydroxy- 6B-methylall0pregnane-3,20-d1one 3,20-b1s-(alkylene ketal) is thereupon hydrolyzed in a water-miscible solvent, preferably in an aqueous-alcohol-acidic medium. As solvent alcohols, methanol and ethanol are the preferred alcohols; however, tertiary butyl alcohol, propyl alcohol, isopropyl alcohol, or dioxane, acetone, or the like may be used as solvent. To the solution of the steroid is then added an organic or inorganic acid, preferably a mineral acid such as sulfuric acid, hydrochloric acid, but also organic acids such as formic, acetic, propionic, toluenesulfonic, may be used. The thus obtained mixture is refluxed, then neutralized with sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or other alkali solutions, and concentrated to give a crude product consisting of l l-oxygenated 5ot,l7a,2l-trihydroxy- 6,8-methylallopregnane-3,20-dione. The crude product can be purified by recrystallization from organic solvents such as acetone, ethyl acetate, Skellysolve B hexanes, methanol, tertiary butyl alcohol, ether, or the like, or mixtures thereof to give pure 11-oxygenated-5u,17a,2ltrihydroXy-6/3-methylallopregnane-3,ZO-dione.

The thus obtained lI-oXygenated-Sa,17u,21-trihydroxy- 6B-methylallopregnane-3,20-dione is thereupon dehydrated. Dehydration can be effected in alkali solution or in acidic solution in the absence or presence of a nitrogen atmosphere. In the preferred embodiment of the present invention alkali dehydration is the preferred one. For this purpose the steroid is dissolved in methanol, ethanol, dioxane, or other convenient solvents, unreactive to the base employed, and the solution purged of oxygen by bubbling nitrogen through the solution, and reacted With a similarly oxygen-free alkali metal base solution. Sodium or potassium hydroxide are the preferred bases; however, alkali metal alkoxides, barium hydroxide, calcium hydroxide or the like, are operative. The amount of base used determines the relative amount of dot-methyl epimer to Gil-methyl epimer produced. If the amount of base is sufiicient to keep the solution alk? ne during the whole reaction period the 6a-methyl epime prevails, if the solution becomes close to neutral, the 6;- methyl epimer is produced. Subsequent treatment with 31101 producing agent, acid or base, of 6B-methylhydrocrj'itisone produces the more active 6a-methylhydrocortisone. The alkaline mixture is then allowed to stand in a nitrogen atmosphere for a period of from four to 48 hours at a temperature between fifteen and forty degrees centigrade to give 11 oxygenated 6 methyl 170:,21 dihydroxy 4 pregnene-3,20-dione. To isolate this 6-methyl steroid, the mixture is acidified, illustratively with acetic acid and the mixture is thereupon concentrated and finally evaporated to dryness. The resulting residue is recrystallized from suitable organic solvents such as acetone, Skellysolve B-hexanes, heptanes, ethanol, methanol, tertiary butyl alcohol, dioxane, ether, acetone, or the like, to give the pure 11- oxygenated 6-methyl-l7a,2l-dihydroxy-4-pregnene-3,20- dione.

Dehydration can also be carried out by reacting the ll-oxygenated 5a,17,21-trihydroxy-6 8-methylallopregmane-3,20-dione with an acid, or with thionyl chloride in pyridine solution to give the corresponding ll-oxygenated G-methyll7a,2 l-dihydroxy-4-pregnene-3 ,20-dione.

Instead of the instant steps of (l) decomposing the metal (Grignard) steroid complex in a neutral solution, (2) hydrolyzing to remove the ketal groups and (3) dehydrating to establish a 4(5)-double bond, the metal steroid complex in the original solution may be decomposed, hydrolyzed and dehydrated in one step by the additon of acid, illustratively dilute aqueous sulfuric acid or aqueous alcoholic acid solution. Temperatures between fifteen to forty degrees and a reaction time between six hours to three days depending on the temperatures employed are useful in this one-step procedure to produce ll-oxygenated 6-methyl-l7a,2l-dihydroxy-4- pregnene-3,20-diones from the corresponding metal complex of ll-oxygenated 6-methyl-5oc, 17a, ZI-trihydroxyallopregnane-3,20-dione.

21-acylates of the thus obtained 6-methylcortisone, hydrocortisone and epi-F compounds and other 6-alkyl and 6-aryl cortisone and hydrocortisone compounds are prepared by the same conventional procedures employed for cortisone, hydrocortisone, and epi F, respectively.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1 5a,6ot-0xid0-11}3,170;,21-trihydroxyull0pregnane-3,20-di0ne 3,20-bis- (ethylene ketal) To a solution of 0.901 gram of l1;3,l7a,21trihydroxy- 5-pregnene-3,20-dione 3,20-bis-(ethylene ketal) in eighteen milliliters of chloroform was added a solution of 331 milligrams of perbenzoic acid in 5 .19 milliliters of chloroform. The resulting solution was allowed to stand in the refrigerator (ca. four degrees centigrade) for a period of 24 hours and thereupon at room temperature for an additional period of 72 hours. The reaction solution was then Washed with five percent sodium bicarbonate solution and Water, was dried over anhydrous sodium sulfate and evaporated to dryness to give 1.031 grams of crude solid. Recrystallization from acetone gave 431 milligrams of product of melting point 230 to 247 degrees centigrade. The mother liquor, after evaporation to dryness, was dissolved in methylene chloride and chromatographed over 25 grams of acid washed alumina. The column was developed with three fractions each of methylene chloride plus five, ten, fifteen, twenty, 25 and fifty percent acetone, acetone, and acetone plus five percent methanol. The acetone plus five percent methanol eluate gave an additional 279 milligrams of high melting product. The high melting material, 5a,6a-oxido-115,l7m,2l-trihydroxyallopregname-3,20-dione 3,20-bis-(ethylene ketal) was three times recrystallized from acetone and methanol giving a melting point of 263 to 268 degrees centrigrade. Other eluate fractions of lower melting point contained the 55,6,6-isomer thereof.

PREPARATION 2 5 0;,601-0Xid0-1 I oz,1 7oc,21-trihydroxyallopregmme-3,20-di0ne 3,20-bis-(ethylene ketal) In exactly the same manner as shown in Preparation 1, 11u,17a,21-trihydroxy-5-pregnene-3,20-dione 3,20-bis- (ethylene ketal) was epoxidized with penbenzoic acid in a chloroform reaction medium to yield a mixture of 5u,6aoxidoand 5fl,6,B-oxido-11a,17u,21-trihydroxypregnane- 3,20-dione 3,20-bis-(ethylene ketal) which was separated by chromatography so as to isolate the desired 5u,6aoxido-l1a,17a,21-trihydroxyallopregnane-3,20-dione 3,20- bis-(ethylene ketal) from the 5,8,6,8-oxido isomer.

PREPARATION 3 5a,6a-0xido-1 7a,21-dihydroxyallopregna-ne-3,11,20- trione 3,20-bis- (1 ,Z-propylene ketal) technique of Preparation 1 yielded 5a,6oc-0XidO-l7oz,2l-

dihydroxyallopregnane-3,11,20-trione 3,20 bis-( 1,2-propylene ketal) and the 5/3,6,B-oxido isomer.

Using as starting material the more commonly available cortisone 3,20-bis-(ethylene ketal) gives the 5a,6a-

separated by one carbon atom such'as 1,3, 2,4, 3,5, and.

the like, with an organic peracid such as, performic, peracetic, perbenzoic, monoperphthalic acid, or the like. For the purpose of this invention starting compounds having the ethylene ketal groups are preferred, since these ketals are generally more easily prepared than ketals producedby the reaction of the 3,20adiketal compounds with higher alkanediols. 1

7 EXAMPLE 1 511,115,] 711,21-tetrahydroxy-6fl-m-ethylallopregnqne F 3,20- dine 3,20-bis-(ethylen e ketal) A solution of 1.115 grams of pc,6 x0Xid O-11/3,17oc,2'1trihydroxyallopregnane-3,20-dione 3,20 bis-(ethylene ketal) in 165 'milliliters of tetrahydrofuran (the tetrahydrofuran. being. purified through distillation over lithiumaluminum hydride) was added dropwise to a solution of 95 milliliters of methyl magnesium bromide in ether (the methyl magnesium bromide being of a four molar concentration). To this mixture was added 5 75 milliliters of benzene, and the reaction mixture was thereupon allowed'to stir and reflux for 26 hours. After cooling, the reaction mixture was poured into 700 milliliters of iced, saturated ammonium chloride solution, stirred for a period of thirty minutes, and the benzene layer separated from the aqueous layer. The aqueous phase was extracted with three ZOO-milliliter portions of ethyl acetate and the extracts'were added to the benzene layer. The combined benzene-ethyl acetate solution was thereupon washed with watergdried over anhydrous sodium sulfate and evaporated to dryness to give 1.314 grams of crude solid. Trituration of material with ethyl ether left 1.0.64 grams of crystalline prod net of melting point 221 to 230 degrees. Recrystallization of this material gave an analytical sample melting at 228 to 233 degrees and rotation [al minus eleven degrees in chloroform of 50t,l1B,1741,21-i6ff8hYdtOXY-6B- methylallopregnane-3,20-dione 3,20-bis-(ethylene ketal).

Analysis.Calcd for C H O z C, 64.70; H, 8.77. Found: C, 64.29; H, 8.69.

EXAMPLE 2 5 0a,] 1,9,1 70,21 -tetrahydroxy-6fl-ethylall0pregriqne- 3,20-diam 3,20-bis-(ethylene ketal) In the same manner as shown in Example 1, 50,6moxido-l 1,8, 17a,2 l-trihydroxyallopregnane-3 ,ZO-dione 3,20- bis-(ethylene ketal), was reacted with ethyl magnesium bromide in ether solution and the thus obtained metalsteroid complex decomposed with aqueous ammonium chloride solution to give the corresponding 5oc,llfi,17ca, 2'1 tetrahydroxy-6,6-ethylallopregnane-3,ZO-dione 3,20-bis- (ethylene ketal).

' EXAMPLE 3 5a,]704,21-trihydr0xy-6fl-methylall0pregnane-3J1,20-

triorie 3,20-bis-(ethylene ketal) In the same manner as shown in Example 1, 5a,6 xoxido-17a,2l-dihydroxyallopregnane-BT, l 1,20-trione 3 ,20- bis-(ethylene ketal) was reacted with methyl magnesium bromide in benzene solution and thethus obtained metalsteroid complex decomposed with aqueous ammonium chloride solution to give 5a,17a,21-trihydroxy-6,8-1nethylallopregnane-3,l1,20-trione 3,20-bis-(ethylene ketal).

EXAMPLE 4 5 0a,] 1 ,17a,21detrahydroxy-(ifi-htethylallopregnane- 3,20- flame 3,20-bis'(ethylene ketal) In the same manner as shown in Example 1, ,6a- 0Xido-11 c,17oc,21-trihydroxyallopregnane-3,ZO-dione 3,20- bis-(ethylene ketal) was reacted with methyl magnesium iodide and the thus obtained metal-steroid complex decomposed with aqueous ammonium chloride solution to give 5a,1 la,17a,21-tetrahydroxy-6B-methylallopregnane- 3-20-dione 3,20-bis-(ethylene ketal).

EXAMPLE 5 5 cr,] 7 0:,21 -tri/zydroxy-d/S-phenylallopregnane-3,1 1,20- trione 3,2 O-bispropylene ketal) In the same manner as shown in Example 1, asol'ution of 5a,6oc oxido l7zx,2l dihydroXyal1opregnane-3,l1,20- trione 3,20-bis-(propylene ketal), dissolved in tetrahydrofuran, Was reacted with a benzene solution of phenyl calcium iodide and the thus obtained metal-steroid complex decomposed with aqueous ammonium chloride solution to give 50,17a,2l-trihydroxy-6fi-phenylallopregnane- 3,11,20-trione 3,20-bis-(propylene ketal).

In the same manner as shown in Examples 1 through 5, other 50c,ll,6,17oc,2l tetrahydroxy-6p?-alkylallopregmane-3,20-dione 3,20-bis-(ethylene ketal), 5a,llu,l7a,21- tetrahydroxy 6 3 alkylallopregnane-3,ZO-dione 3,20-bis- (ethylene ketal) and 5m,17a,21-trihydroxy-6,B-alkylallopregnane-3,1l,20-trione 3,20-bis(ethylene ketal) are prepared by reacting the corresponding allopre'gnanes, 50,6ot oxide 17 0:,21 dihydroxyallopregnane-3,ZO-dione 3,20-bis-(ethylene ketal), oxygenated in the ll-position, with a metal alkyl more specifically an alkyl metal halide such as a Grignard reagent, for example methyl, ethyl, propyl, isopropyl, butyl pentyl, hexyl, and phenyl magnesium bromides and iodides or similar alkyl cadmium and calcium bromides or iodides. Representative -6- alkylated allopregnanes thus prepared include: 5a,ll,6, 17u,2l tetrahydroxy propylallopregnane-3,ZO-dione 3,20-bis (ethylene ketal), 50,1lfi,17a,21 tetrahydroxy- 6fi-butylallopregnane-3,ZO-dione 3,20-bis- (ethylene ketal) 5 oc,11B,17a,21 tetrahydroxy 6B isobutylallopregnane- 3,20-dione 3,20-bis-(ethylene ketal), 5a,ll;3,17u,21-tetrahydroxy-6/8-pentylallopregnane-3,ZO-dione 3,20-bis-(ethylene ketal) 5a,l1,8,17ot,21 tetrahydroxy 6/3 hexylallopregnane-3,20-dione 3,20-bis-(etl1ylene ketal), 5a,ll/3, Hall-tetrahydroxy 6,8 phenylallopregnane-3,ZO-dione 3,20-bis-(ethylene ketal); 5a,1la,17a,2l-tetrahydroxy- SB-ethylallopregnane-B,20-dione 3,20-bis- (ethylene ketal) 5a,11oc,17oc,21 tetrahydroxy 6,8 propylallopregnane- 3,20-drone 3,20-bis-(ethylene ketal), 5a,lla,l7a,2ltetrahydroxy 6,8 isopropylallopregnane-3,20-dione 3,20 bis- (ethylene ketal), 50,lla,17oc,2l-tetrahydroxy-6fi-butylallopregnaue-3,20-dione 3,20-bis-(ethylene ketal), 5oz, 11a,l70c,2l tetrahydroxy 6,8 pentylallopregnane 3,20.- dione 3,20-bis-(ethylene ketal), 5a,11o:,l7oc,21-tCtr3.hydroxy-6/8-hexylallopregnane-3,ZO-dione 3,20-bis-(ethylene ketal), 5a,11a,17zx,21 tetrahydroxy 6B phenylallopregnane-3,20-dione 3,20-bis(ethylene ketal), the 2la-monoacylates and lla,2l-diacylates thereof wherein the acyl group is of an organic carboxylic acid and preferably of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms or of a benzene-sulfonic acid; 50:, Hall-tetrahydroxy 6B phenylallopregnane-3,ZO-dione 3,20-bis-(ethylene ketal), 5a,17a,21-t1ihydroxy-6/3-propylallopregnane-3,l1,20-trione 3,20-bis (ethylene' ketal), 5oz,17ot,21 trihydroxy-6/3-isopropylallopregnane 3,11,20,- trione 3,20-bis-(ethylene ketal), 5a,l7a,2l-trihydroxy- 6fl-butylallopregnane 3,11,20 t-rione- 3,20 bis-.( ethylene ketal) 5 ,17a,21-trihydroxy-65-pentylallopregnane-3,1 l, 20-trione 3,20-bis-(ethylene ketal), 5u,l7a ,2 l-trihydroxy- 6B hexylallopregnane 3,11,20 trione 3,20'-bi s.-(ethyl ene ketal), and the like, including those 6B-alkylallopregnanes having ketal groups in positions 3 and 20 such as exemphfied in the preparations of starting materials.

EXAMPLE 6 5 a,] 1 3,1 7a,21-tetmhydr0xy-6B-methylallopregnane- 3,20-di0ne A solution was prepared containing 468 milligrams of oc,1 1fl,l7oc,21 tetrahydroxy 6,8 methylallopregnane- 3,20-dione 3,20-bis-(ethylene ketal), 38 milliliters of methanol and 7.7 milliliters of 2 Normal sulfuric acid. This solution was refluxed for a period of thirty minutes, then neutralized with dilute sodium bicarbonate solution (about 100 milliliters of five percent solution) and concentrated under reduced pressure at 55 degrees centigrade to about 35 milliliters of volume. A product crystallized upon cooling and was recovered by filtration. This product was recrystallized from acetonerSkellysolve' B hexanes to give an analytical pure sample of 5a,11/3, 17a,21-tetrahydroxy 6B methylallopregnane-3,20-dione of melting point 240 to 244 with decomposition and retation [al plus forty degrees in dioxane.

Analysis.--Calcd. for C H O C, 66.98; H, 8.69. Found: C, 66.84; H, 8.86.

EXAMPLE 7 5 01,1 118,1 70,21 -tetrahydroxy-6 3-ethylall0pregnane 3,20-di0ne In the same manner as shown in Example 6, 5a,11 8, 170:,21 tetrahydroxy 6B ethylallopregnane 3,20-dione 3,20-bis-(ethylene ketal) was hydrolyzed with dilute sulfuric acid in ethanol solution to give 5a,l1/3,l7a,2l-tetrahydroxy-6fi-ethylallopregnane-3,ZO-dione.

EXAMPLE 8 5 00,] 704,21 -trihydroxy-6,B-methy lallo pregnane- 3,11,20-tri0ne In the same manner as shown in Example 6, 50:,17cc,21- trihydroxy- 6 ,B-methylallopre gnane-3 l 1,20-trione 3 ,20-bis- (ethylene ketal) was refluxed in sulfuric acid solution in methanol to yield 5m,170;,21-trihydroxy-6B-methylallopregnane-3 ,1 1,20-trione.

EXAMPLE 9 511,11 a,17a,21 telrahydroxy-lifi-methylallopregnane-3,20-

dione In the same manner as shown in Example 6, 511,110, 17oc,2 l-tetrahydroxy-6 8-methylallopregnane 3,20 dione 3,20-bis-(ethylene ketal) was hydrolyzed by refluxing the diketal with dilute hydrochloric acid in methanol solution to give 5oc,11oc,17oa,21 tetrahydroxy 6B methylallopregnane-3,20-dione.

EXAMPLE 10 5zx,17ot,21 trihydroxy 6B phenylallopregnane-3,11,20-

trione In the same manner as shown in Example 6, 5a,17a,2ltrihydroxy 6/3 phenylallopregnane-3,11,20-trione 3,20- bis-(propylene ketal) was refluxed with sulfuric acid in methanol solution to give 5a,17a,2l-trihydroxy-6/3-phenylallopregnane-3,1 l,20trione.

In the same manner as shown in Examples 6 through 10, inclusive, acid hydrolysis of 5a,11fi,17a,2l-tetrahydroxy-6B-alkylallopregnane-3,20 dione 3,20-bis-(ethylene ketal) 5 oc,1 10c, 17 a,2l-tetrahydroxy-6fl-alkylallopregnane- 3,20-dione 3,20-bis-(ethylene ketals), the 2la-monoesters and 11a,21-diesters thereof, and 5a,17a,2l-trihydroxy-6flalkylallopregnane-3,l1,20-trione 3,20-bis-(ethylene ketal) as well as those 6B-alkylallopregnane-3,20-dione 3,20-bis- (ketals) wherein the ketal group is other than ethylene such as shown in the preparation of starting compounds can be hydrolyzed to give the corresponding ll-oxygenated 5a,l7a,2l-trihydroxy-6B-alkylallopregnane-3,20-diones, such as, for example, 50,1l5,17a,2l-tetrahydroxy-GB-propylallopregnane-3,20-dione, 511,1 1fl,17oc,21 tetrahydroxy .10 6fi-butyla1lopregnane-3,20-dione, 5u,11;3,17oc,21 tetrahydroxy-6fi-isobutylallopregnane-3,ZO-dione, 5a,11fi,17a,21- tetrahydroxy 6B-pentylallopregnane 3,20 dione, 5a,11fl,

17a,21-tetrahydroxy-6p-hexyla1lopregnane-3,20-dione, 50:, 11311121 tetrahydroxy 6B phenylallopregnane 3,20

dione, 50:,11a,17 x,21-tetrahydroXy-613-ethylallopregnane-3,

20-dione, 5a,1la,17a,2l-tetrahydroxy-6fl propylallopregnane-3,20-dione, 50:,1 la,1701,21-tetrahydroxy6 9-isopropy1- allopregnane-3,20-dione, 50,11a,17u,21-tetrahydroXy 6,8- buty1allopregnane-3 ,20-dione, 500,1 10c, 17a,21-tetrahydroxy- 6/3-pentylallopregnane-3,20-dione, 5u,11a,l7a,21-tetrahydroxy-6fi-hexylallopregnane 3,20 dione, 5a,11oc,17u,21- tetrahydroxy-6fi-phenylallopregnane 3,20 dione, the 21- monoacylates and 1la,21-diacylates thereof wherein the acyl group is of an organic carboxylic acid and preferably of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, or of a benzenesulfonic acid whenever such esters are stable to acid hydrolysis; 5a,17u,21- trihydroxy-6;8-ethylallopregnane 3,11,20 trione, 50:,17u, 21-trihydroxy-6,8-propylallopregnane 3,11,20 trione, 50c, 17,21trihydroxy-Gfi-isopropylallopregnane 3,11,20 trione, Su,17a,21-trihydroxy-6/3-butylallopregnane 3,11,20- trione, 5a,17u,2l-trihydroxy 6fl-pentylallopregnane-3,l1, 20-trione, 5a,17o,21-trihydroxy-6[3 hexylallopregnane 3, 11,20-trione, and the like, including those GB-alkylallopregnanes having ketal groups in positions 3 and 20 as exemplified in the preparations of starting materials.

EXAMPLE 11 6 oa-methylhydrocortisone A stream of nitrogen was bubbled through a solution of 429 milligrams of 50,11fl,17u,21-tetrahydroxy-6B- methylallopregnane-3,20-dione, contained in milliliters of denatured absolute alcohol, for a period of ten minutes. To this solution was added 4.3 milli1iters of 0.1 normal sodium hydroxide solution which had likewise been treated with nitrogen. The mixture was allowed to stand in a nitrogen atmosphere for a period of eighteen hours and was thereupon acidified with acetic acid, and concentrated to dryness under reduced pressure at 55 degrees centigrade. The residue weighing 417 milligrams was recrystallized from acetone-Skellysolve B hexanes to give in two crops 249 milligrams melting between 184 and 194 degrees centigrade An analytical sample was prepared melting at 203 to 208 degrees centigrade and consisting of pure 6u-methylhydrocortisone. Rotation [al plus degrees (in acetone).

Analysis.Calcd. for C H O C, 70.18; H, 8.57.

Found: C, 70.32; H,

r xgggr 242-243 Infrared absorption spectrum in chloroform: 20-keto cm.- 1700 Conjugated 3-keto cm.- 1655 M-double bond 1600 Infrared absorption spectrum in Nujol:

EXAMPLE 13 n-methyl-lla,17a,21:trihydrxy 4-pregnene-3,20-di 0ne (.6-methyl-11-epi F) I In the same manner as shown in Example 11, oz, 1la, 17 }21-tetrahydroxy-fiB-methylallopregnane 3,20 drone was treated with a methanolic solution of potass um hydroxide to give 6u-methyl-lla,17a,2l-trihydroxy-4 pregnene-3,20-dione (6-methyl epi F).

EXAMPLE l4 fia-methylcortisone In the same manner as shown in Example 11, 504,17, 21fltrihydroxy-6 3-phenylallopregnane 3,11,20rtrione was treated with'sodium hydroxide in denatured ethyl alcohol to g ive 6-phenylcortisone.

In the same manner dehydrating with an alkali hydroxide, alkali alkoxide or a mineral'acid in alcoholic solution other 1l-oxygenated-Sa,17a,21-trihydroxy-6fi-alkylallopregnane-3,20-diones produced the corresponding lloxygenated 6a-alkyl- 17 0:,21 dihydroxy-4-pregnene 5 3,20- dion es such as 6 qpr opylhydrocortisone,' 6u butylhydrocortisone, og-isobutylhydrocortisone, ou-pentylhydrocortisone, r6o hexylhydrocortisone, 6u-phenylhydrocortisone, 6t-ethylcortisone, 6a propylcortisone,' 6 m-isopropylcortisone, Ga-butylcortisone, 6o -pentylcortisone, 6othexylcortisone, 1'1,17a,2l trihydroxy-6ot-ethyl 4 pregnene-3, ZO-dion e, 11a,17a,21-trihydroxy-6a-propyl 4-pregnene-3, 20-dione, 1la,17e,2l-trihydroxy-6wisopropyl-4-pregnene 3,20- dione, l1or,l711,2l-trihydroxy-ou-butyl 4 preghene- 3,20-dione, l loc,17oc,2 l-trihydroxy-6a-pentyl-4-pregnene-3, 20-dione, 11e,l7u,2l-trihydroxy 6ot-hexyl 4-pregnene-3, ZO-dione, l1e,171;,2l-trihydroxy-6d-phenyl-4 pregnene-S, 20-dione. a a i f EXAMPLE 16 6/3-methylhydr0cortis0ne A solution was prepared containing 27.5 grams of 5a,l1fi,17u,21 tetrahydroxy 6B methylallopregnane- 3,20-dione in 6500 milliliters of ethanol denatured with methanol. The solution was freed of air oxygen by bubbling oxygen-free nitrogen through it for a period of fifteen minutes. To this solution was added a similarly air y -f ee p epa e ut o of one-t n no m sodi m yd x d 0 mi ili e he so u was allowed to stand at room temperature (about 22 to 24 d re s cen i asle) in an nert n tro en a m p re r a period of twenty hours and was then acidified with fourteen milliliters of acetic acid. The thus obtained acid solution was evaporated at about fifty to sixty degrees centigrade in vacuo, the thus produced residue dissolved in 200 milliliters of ethyl acetate and 200 milliliters of water, the water layer separated from the organic layer and discarded, the organic layer washed with 350 milliliters of five percent aqueous sodium bicarbonate solution, then three times with water and thereupon dried over anhydrous sodium sulfate and concentrated to a volume of 180 milliliters. After cooling the 180 milliliters of solution in a refrigerator (about five degrees centigrade), the solution was filtered giving 11.9 grams of material. This material was redissolved in 500 millite of e h ce at the eth a et te soluti was concentrated to 150 milliliters, refrigerated as before to g ve ram rude fi-m hy ydr wr s0n of melting point 220-223.

12 Recrystallization of the crude 6B-methy1hydrocortisone three more times from ethyl acetate gave an analytical sample of 618-methylhydrocortisone with melting point 223 to 227 degrees centigrade, rotation [al plus 105 degrees in acetone; ultraviolet absorption gsg ethnnol Analysis.-Calcd. for C H O C, 70.17; H, 8.57. Found: C, 70.54; H, 8.91.

EXAMPLE 17 6u-methylhydrocortisone from 6,6-methylhydrocortisone A solution was prepared containing 9.12 grams of crude Gfi-methylhydrocortisone (impurity 6 t-methylhydrocortisone) in 325 milliliters of methanol. To solution at room temperature was added milliliters of 2 normal aqueous sulfuric acid solution. The reaction mixture was allowed to stand overnight (eighteen hours) at room temperature, thereupon neutralized with 225 milliliters of aqueous five percent sodium bicarbonate solution and then concentrated on the water bath at about fifty to degrees centigrade to a volume of about 175 milliliters. The mixture was then filtered, and the thus recovered precipitate washed with 250 milliliters of water, and dried in a vacuum oven at degrees centigrade to give 7.72 grams of solids of melting point 195 to 205 degrees centigrade. The aqueous solution was extracted with three ISO-milliliter portions of ethyl acetate, the extracts were combined, washed with three lSO-milliliter portions of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure at 55 degrees centigrade to give a residue. This residue was combined with the 7.72 grams of solid, previously obtained and recrystallized from ethyl acetate to give in two crops 6.44 grams of 6a-methylhydrocortisone of ninety to 95 percent purity. Recrystallization of one gram of this material (twice from ethyl acetate) gave 6u-rnethylhydrocortisone of melting point 200-207 degrees centigrade and [0:1 plus 114 degrees in acetone.

Ultravoilet absorption 242 mp, E -15,025.

Instead of a mineral acid such as sulfuric hydrochloric, chloric, dilute nitric, perchloric acid or the like, a base, preferably an alkali metal hydroxide such as sodium or potassium hydroxide or carbonate, or other acidic or basic enolyzing agents capable to temporarily enolyze the 3-keto group to a 3-enol group can be used to epimerize the 6fl-methylhydrocortisone to the more stable 6a-methylhydrocortisone. The conversion with a base can be carried out as follows:

One gram of GB-methylhydrocortisone, dissolved in forty milliliters of methanol, was treated at room temperature with 0.5 gram of sodium hydroxide, dissolved in three milliliters of water. The mixture was allowed to stand for sixteen hours overnight, was then diluted with 200 milliliters of Water, neutralized with five percent aqueous hydrochloric acid, and extracted with three -milliliter portions of methylene chloride. The methylene chloride extracts were washed with water several times, dried over anhydrous sodium sulfate, evaporated and the thus obtained residue recrystallized from acetone to give 6u-methylhydrocortisone.

EXAMPLE 18 6u-methylhydrocortisone acetate A mixture was prepared containing 164 milligrams of 6a-methylhydrocortisone in one milliliter of pyridine and one milliliter of acetic anhydride. This mixture was allowed to stand at room temperature 22 to 24 degrees centigrade) for a period of sixteen hours, was thereupon poured into ten milliliters of ice water and the resulting aqueous mixture was extracted with three 25-milliliter portions of methylene chloride. The combined methylene chloride solutions were washed, dried over anhy 119 .5 waive ulf e nd q sat ra hed o r fiftee 13 grams of Florisil. The fraction eluted with Skellysolve B plus twenty and thirty percent acetone (92 milligrams) was evaporated and the thus obtained material crystallized three times from acetone-Skellysolve B hexanes to give pure 6a-methy1hydrocortisone Zbacetate melting at 213 to 214 degrees centigrade.

Analysis.Ca1cd. for (3 1-1 C, 68.87; H, 8.19. Found: C, 68.60; H. 8.41.

Infrared absorption spectrum in Nujol mineral oil Cm." OH 3440 Acetate carbonyl 1743 20-keto 17 20 Conjugated S-keto 1654 A -double bond 1616 Acetate C-O- bond 1234 EXAMPLE 19 6a-methylc0rtis0ne benzoate A mixture of 500 milligrams of 6a-methylcortisone, five milliliters of pyridine and five milliliters of benzoyl chloride was allowed to stand at room temperature for a period of eight hours. Thereafter the mixture was poured into excess of water, the water extracts neutralized with sodium bicarbonate and thereupon the mixture refrigerated. The mixture was then filtered and the thus obtained 6oa-methylcortisone benzoate recrystallized from methanol to give pure 6a-methylcortisone benzoate.

EXAMPLE 20 6rx-methyl-1 1 0a,] 7a-dihydroxy-21-trimethylacetoxy- 4-pregnene-3,20di0ne A mixture of 500 milligrams of 6w-methyl-11u,17a,21- trihydroxy-4-pregnene-3,ZO-dione in ten milliliters of pyridine was allowed to stand at room temperature for four hours with 0.5 milliliter of trimethylacetyl chloride. Thereafter the mixture was poured into excess of water and extracted with methylene chloride. The methylene extracts were washed with water, dried and evaporated and the thus obtained residue recrystallized from acetone Skellysolve B hexane solutions to give 6a-methyl-11a, 17a dihydroxy 21 trimethylacetoxy 4 pregnene- 3,20-dione.

EXAMPLE 21 6a-methyl-1 7a-hydr0xy-1l 0:,21-diacetoxy-4-pregnene- 3,20-dione In the same manner as shown in Example 18, 6amethyl 1la,17 x,21 trihydroxy 4 pregnene 3,20- dione was acetylated with acetic anhydride in pyridine solution to give the diester, 6a-methyl-17a-hydroxy-11a, 21-diacetoXy-4-pregnene-3,20-dione.

EXAMPLE 22 d-methylcortisone 21 -trimethylacetate EXAMPLE 23 In the same manner as given in Examples 18 and 19, treating in pyridine solution:

(a) 6ec-methylhydrocortisone with propionic anhydride yielded 6u-methylhydrocortisone 21-propionate.

(b) 6a-methylhydrocortisone with butyric anhydride yielded 6ct-methylhydrocortisone 21-butyrate.

(c) fiu-methylhydrocortisone with Valerie anhydride yielded 6a-methylhydrocortisone 2l-valerate.

(d) 6a-rnethylhydrocortisone with hexanoyl bromide yielded 6u-rnethylhydrocortisone 21-hexanoate.

(e) 6a-methylhydrocortisone with heptanoyl bromide yielded 60t-1T16thYihYdI'OCOftlSOH6 21-heptanoate.

(f) 6a-rnethylhyclrocortisone with octanoyl chloride yielded 6a-methylhydrocortisone 21-octanoate.

(g) '6a-methylhydrocortisone with benzoyl chloride yielded 6ot-rnethylhydrocortisone 21-benzoate.

(h) 6a-methylhydrocortisone with phenylacetyl chloride yielded Gar-methylhydrocortisone 2l-phenylacetate.

(i) 6oa-methylhydrocortisone with B-cyclopentylpropionyl bromide yielded 6a-methylhydrocortisone 21-(flcyclopentylpropionate) (j) 6a ethylhydrocortisone with acetic anhydride yielded 6u-ethylhydrocortisone acetate.

(k) 60c p-ropylhydrocortisone with acetic anhydride yielded 6-propylhydrocortisone acetate.

(1) 6a-isopropy1hydrocortisone with acetic anhydride yielded 6a-isopropylhydrocortisone acetate.

(In) 6u-butylhydrocortisone with acetic anhydride yielded 6ot-butylhydrocortisone acetate.

(11) 6a-phenylhydrocortisone with acetic anhydride yielded 6a-phenylhydrocortisone acetate.

(0) 6ot-methylcortisone with acetic anhydride yielded 6a-methylcortisone 21-acetate.

(p) 60: methylcortisone with propionic anhydride yielded 6a-methylcortisone 2l-propionate.

(q) 6u-methylcortisone with tertiary butyl acetyl chloride yielded 6wmethylcortisone 2l-tertiary butyl acetate.

(r) 6a-methylcortisone with 2-furoyl chloride yielded 6ot-methylcortisone 2l-(2-furoate) (s) 6a-methylcortisone with nicotinyl bromide yielded 6a-methylcortisone 21-nicotinate.

(t) 6oc-phenylcortisone with acetic anhydride yielded 6uphenylcortisone 21-acetate.

(u) a-ethylcortisone with butyric anhydride yielded 6a-ethylcortisone 2l-butyrate.

(v) 6a-propylcortisone with hexanoyl chloride yielded 6u-propy1cortisone 21-hexanoate.

(w) 60a isopropylcortisone with benzoyl chloride yielded 6a-isopropylcortisone 21-benzoate.

(x) 6a-butylcortisone with toluenesulfonyl chloride yielded 6a-butylcortisone 21-toluenesu1fonate.

(y) 6oc-pentylcortisone with para-chlorobenzenesulfonyl chloride yielded 6a-peutylcortisone 21-para-chlorobenzenesulfonate.

(z) 6oa-hexylcortisone with cinnamyl chloride yielded 6oc-hexylcortisone 21-cinnamate.

EXAMPLE 24 In the same manner as shown in Example 20, reacting in pyridine solution:

(a) 604 methyl 11a,17a,21 trihydroxy 4- pregnene-3,20-dione with triethylacetyl chloride yielded essentially the 60: methyl 11u,17 dihydroxy 21 triethylacetoXy-4-pregnene-3,ZO-dione.

(b) 6oz methyl 11a,17ot,2l trihydroxy 4 pregnene-3,20-dione with dineopentylacetyl chloride yielded essentially the 6ot-methyl-1la,l7-dihydroxy-2l-dineopentylacetoXy-4-pregnene-3,20-dione.

(0) 6oz ethyl 1lot,17u,21 trihydroxy 4 pregnene- 3,20-dione with trimethylacetylchloride yielded essentially the 600 methyl 11a,17 dihydroxy 21 trimethylacetoXy-4-pregnene-3,ZO-dione.

(d) 611 phenyl 11a,17oc,21 trihydroxy 4 pregnene-3,20-dione with trimethylacetyl chloride yielded essentially the 6m phenyl 1104,17 dihydroXy 21 trimethylacetoxy-4-pregnene-3,ZO-dione.

The 6a-alkyl-11-epi hydrocortisone 21-esters can be oxidized as shown in Example 20, to give the corresponding 6a-alkylcortisone 21-esters. Hydrolysis of Eon-alkylcortisone 2l-ester, dissolved in alcohol, with a base such as sodium or potassium hydroxide or carbonate, preferably in a nitrogen atmosphere, gives the free 6a-alkylcortisone.

6a-alkylcortisones may also be prepared by oxidation of the corresponding 6ot-alkylhydrocortisone with a N- haloacidamide or N-haloacidimide, such as shown in Example 27.

EXAMPLE 26 6fl-methylhdrocortisone acetate In the same manner given in Example 18, treating 6emethylhydrocortisone with acetic anhydride in pyridine solution at room temperature yields 6,8-methylhydrocor- EXAMPLE 27 6a-methylcortis0ne To 760 milligrams (2.02 millimoles) of 6-methylhydrocortisone (6-methyl-115,17a,2l-trihydroxy 4 pregnene- 3,20-dione) in 32 milliliters of methanol was added 0.67 milliliter of pyridine, 1.34 milliliters of water and 560 milligrams (4.04 millimoles) of N-bromoacetamide. The reaction mixture was held at twelve degrees centigrade overnight when titration of an aliquot indicated that approximately 1.1 mole equivalents of oxidant had been used. At this time sixty milliliters of a dilute solution of sodium sulfite (containing 400 milligrams of sodium sulfite) was added to destroy excess N-bromoacetamide and the mixture was concentrated under reduced, pressure to about 55 milliliters until copious crystallization occurred. The mixture was cooled to zero degrees centigrade, maintained at this temperature for three hours and filtered to yield 610 milligrams of 6amethylcortisone.

Since the product gave a positive Beilsteintest, it was dissolved in 36 milliliters of acetic acid and treated with 1.2 grams of powdered zinc at room temperature for two hours. The mixture was filtered and the filtrate concentrated to ten milliliters under reduced pressure. addition of fifty milliliters of water caused crystallization. The crystals were filtered off and washed with water and dried to yield 360 milligrams of 6-methylcortisone of melting point 207-2075. Recrystallization from acetone gave 230 milligrams of melting point 212.5-215 degrees. The infrared absorption spectrum of 6a-methylcortisone in Nujol mineral oil is as follows:

0H cn1.- 400 3, 305 11- and -keto cm.- 1, 717 1, 700 conjugated 3-keto cm.- 1, 652 A double bond cur- 1, 604

For intramuscular use or any use where water soluble esters or salts of water soluble esters of 6-methylcortisone or 6-methylhydrocortisone are desired, acid esters such as polybasic acids, illustratively the succinate, hemi-(fifidimethylglutarate) or alkali (sodium) salts thereof are prepared as shown in Example 28 through 31.

To a stirred solution of. 2:5 grams of succinic anhydride in 25 milliliters of pyridine was added 2.0 grams of-Gmmethylhydrocortisone. Stirring'was continued until the 6amethylhydrocortisone was completely dissolved. After standing overnight the reaction mixture was slowly poured into a vigorously stirred mixture of thirty milliliters of concentrated hydrochloric acid, 102 milliliters of water and 127 grams of ice. Stirring was continued for 'one'hour and the crude crystalline, 6a-methylhydrocortisone 21-hemisuccinate,- was separated by filtration. The product was washed on thefilter with water until the filtrate had a pH of 4.0, dried and recrystallized from milliliters of methyl ''ethyl ketoneand 36 millilitersof Skellysolve B hexanes to give pure oa-methylhydrocortisone ZI-hemisuccinate.

Using the 6 3-methyl epimer results in the corresponding 6fl-methylhydrocortisone ZI-hemisuccinate.

, EXAMPLE 29. 6a-m ethylhydrocortisone 21 -hemisuccinate sodium salt Sodium hydroxide solution (0.1 normal) was slowly added to a stirred solution of two grams of 6u-methylhydrocortisone ZI-hemisuccinate in fifty milliliters of acetone until the pH rose to 7.4. During the addition of NaOH solution, 100 milliliters of water was alsoadded. Thefsolution was concentrated at 25 degrees Centigrade under vacuum to remove the acetone. The resulting aqueous solution of 6amethylhydrocortisone 21-hemisuccinate sodium salt was filtered, freeze-dried and recrystallized to give pure 6a-methylhydrocortisone 21,- hemisuccinate sodium salt. 7

Using as starting material 6fl-methylhydrocortisone 21- succinate gave the 6fl-methylhydrocortisone 21-hemisuccinate sodium salt.

In the same manner as shown in Examples 28 and 29, the ZI-hemisuccinate of 6u-methylcortisone and the sodium salt can be prepared or by starting with the 6B- epirner the 21-hemisuccinate of G/B-methylcortisone and the sodium salt thereof can be prepared.

EXAMPLE 30 6a-methylhydrocortisone 21-(3,;3-dimethylglutamte) To a solution of 260 milligrams of [3,B-dimethylglutaric anhydride in two milliliters of pyridine was added 200 milligrams of 6oz-methylhydrocortisone. The mixture was stirred until the 6a-methylhydrocortisone was completely dissolved and the flask was flushed with nitrogen. The reaction was allowed to stand overnight for eighteen hours and was then slowly poured into a stirred cold solution of 2.4 milliliters of concentrated hydrochloric acid and eighteen milliliters of water. The miXture was extracted with three five-milliliter portions of ethyl acetate, the ethyl acetate layer Washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated to 1:5 milliliters under reduced pressure. Thereto was added one milliliter of Skellysolve B hexanes and the mixture allowed to cool to zero degrees centigrade. After 24 hours the mixture was filtered to yield crystals of 6u-methylhydrocortisone 21-(p,s-dimethylglutarate). The infrared spectrum of 6a-methylhydrocortisone 21-(fi,B-dimethylglutarate), measured in Nujol mineral oil, corresponded to the postulated structure of the compound. a

Using as starting material 6fi-methylhydrocortisone results. in 6fl-methylhydrocrotisone 2l-(p,[3dimethylglutarate).

In the same manner as shown in Example 30, treating 6-rnethylcortisone (or or ,8) with 18,,8-dimethylglutaric anhydride yields 6-methylcortisone 21-(,8,;3-dimethy1glutarate) (61x or 65).

, A-metal salt of 6u-methylhydrocortisone 21-(B,/3-dimethylglutarate) may be prepared as illustrated below:

EXAMPLE 31 da-methylhydrocortisone 21-(flp-dimethylglutarate) sodium salt A sodium hydroxide solution (0.1 normal) was slowly added to a stirred solution of two grams of Got-methylhydrocortisone 21-(fi,B-dimethylglutarate) in 100 milliliters of acetone until the pH rose to 7.4. During the addition of the sodium hydroxide solution, 100 milliliters of water was also added. The solution was concentrated at 25 degrees centigrade under vacuum to remove the acetone. The resulting aqueous solution was filtered and freeze dried to give 6a-methylhydrocortisone 21-(5,;3-dimethylglutarate) sodium salt.

In the same manner given in Example 31, 6a-methylcortisone 21-( 8, 8-dimethylglutarate) sodium salt is prepared by reacting a solution of 6ot-methylcortisone 2l- (fifi-dimethylglutarate) with a solution of sodium hydroxide.

Using in the manner indicated in Examples 30 and 31, the 6fl-epimers, results in the production of 6B-methylhydrocortisone ZI-(BJB-dimethylglutarate) and the sodium salt thereof or with the 6(3-methylcortisone as starting material in the production of the 6,3-methylcortisone 21-(;3,B-dimethylglutarate) and the sodium salt thereof.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

18 1. A compound of the formula:

o=o ---oH wherein R is selected from the group consisting of 1118- hydroxy and ll-keto, and wherein R" is selected from the group consisting of hydrogen and acyl, in which the acyl group is of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

. 6-methylhydrocortisone.

. 6a-methylhydrocortisone.

. 6-methylcortisone.

6ot-methylcortisone.

. G-methylhydrocortisone ZI-acetate.

. a-methylhydrocortisone 21-acetate.

. 6ot-methylhydrocortisone 2l-hemisuccinate.

References Cited in the file of this patent Ehrenstein: Journal of Organic Chemistry, 8, 1943, pages 83-94.

Madaeva: Chem. Abstr., 34, 7292 (1940).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,897,217 July 28, 1959 George B. Spero It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l, line 20, for compounds read --compound-; line 60 for generaly read -generally; column 5, line 40, beginning with epimer to, strike out all to and including The alkaline in line 45, and insert insteadepimer to GB-methyl epimer produced. If the amount of base is sufiicient to keep the solution alkaline during the whole reaction period the Gut-methyl epimer prevails, if the solution becomes close to neutral, the GB-methyl epimer is produced. Subsequent treatment with an enol producing agent, acid or base,

of GB-methylhydrocortisone produces the more active 6a-methylhydrocortisone.

The alkaline column 8, lines 66 to 68, for 5a,17a,21-tetrahydro -6B-phenylallopregnane-3,20-dione 3,20-bis-(ethylene ketal), read -5a,17,21-trihy oxy-6B-ethylal10pregnane-3,11,20- trione 3,20-bis- (ethylene ketal),-; column 15, line 16, for bfi-methylhdrooortz'sone read 6,B-methylhydrocortz'sone; line 75, for Example read --Examples; column 16, line 68, for "BB-methylhydrocrotisone read -6B-methylhydrocortis0ne--.

Signed and sealed this 9th day of February 1960.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oficer. Commissioner of Patents. 

1. A COMPOUND OF THE FORMULA: 